One of the outstanding problems in temporal lobe epilepsy is to understand the mechanisms contributing to treatment-resistant seizures that involve the hippocampus, and then to design mechanism-based novel therapeutic approaches. Such treatments are important both to control intractable seizures and to ameliorate the hippocampal-dependent memory deficits associated with epilepsy. This project will challenge current dogma that focuses on the role of neurons in the three major regions of the hippocampus: dentate gyrus, CA3 and CA1. Instead, this proposal focuses on area CA2, a relatively small region of hippocampus that has received little attention but is known to survive relatively intact in epileptic patients and may serve as a hyperexcitable seizure focus. Experimental tools developed in the laboratories of the two Principal Investigators now enable the direct investigation of the importance of CA2 in mouse models of epilepsy by employing a mouse line that selectively expresses the bacterial enzyme Cre recombinase only in CA2 neurons. Viral vectors that express tetanus toxin (or other proteins that can silence neural activity) in the presence of Cre will be injected into the hippocampus of these mice to turn off CA2 activity. In this manner it will be possible to test whether CA2 controls the pharmacological induction of seizures in the healthy brain and/or spontaneous seizures in the diseased, epileptic brain. The methods alone will advance the field because they are novel and provide more specificity and control than has been previously possible in epilepsy research. Moreover, by evaluating the role of CA2 in epilepsy, this project will result in the potential validation of sevral novel drug targets highly enriched in CA2 neurons.